All Phenotypes Tnf<tm2Gkl> MGI Mouse

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Phenotypes associated with this allele

Allele Symbol
Allele Name
Allele ID

Tnf^tm2Gkl
targeted mutation 2, George Kollias
MGI:2388715

Summary

29 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Tnf^tm2Gkl/Tnf^tm2Gkl	involves: 129S/SvEv * C57BL/6	MGI:3622060
ht2	Tnf^tm2Gkl/Tnf⁺	B6.129S-Tnf^tm2Gkl/Jarn	MGI:5702925
ht3	Tnf^tm2Gkl/Tnf⁺	involves: 129S/SvEv * C57BL/6	MGI:3622061
ht4	Tnf^tm2Gkl/Tnf⁺	involves: 129S/SvEv * C57BL/6 * CBA	MGI:3775436
ht5	Tnf^tm2Gkl/Tnf⁺	involves: 129S/SvEv * C57BL/6J	MGI:3629514
ht6	Tnf^tm2Gkl/Tnf⁺	involves: 129S/SvEv * C57BL/6 * SPRET/Ei	MGI:3622071
ht7	Tnf^tm1Gkl/Tnf^tm2Gkl	involves: 129S/SvEv * C57BL/6	MGI:3622062
cn8	Tnf^tm2Gkl/Tnf⁺ Tnfrsf1b^tm1.1Gkl/Tnfrsf1b^tm1.1Gkl Tg(Col6a1-cre)1Gkl/0	involves: 129S/SvEv * C57BL/6 * C57BL/6J * CBA	MGI:6195612
cn9	Tnf^tm2Gkl/Tnf⁺ Tnfrsf1a^tm2Gkl/Tnfrsf1a^tm2Gkl Tg(Col6a1-cre)1Gkl/0	involves: 129S/SvEv * C57BL/6 * C57BL/6J * CBA	MGI:6195614
cn10	Tnf^tm2Gkl/Tnf⁺ Tnfrsf1a^tm2Gkl/Tnfrsf1a^tm2Gkl Tg(Col6a1-cre)1Gkl/?	involves: 129S/SvEv * C57BL/6 * CBA	MGI:3775437
cx11	Mapk11^tm1Jsca/Mapk11^tm1Jsca Tnf^tm2Gkl/Tnf⁺	involves: 129P2/OlaHsd * 129S/SvEv * C57BL/6	MGI:3622058
cx12	Tnf^tm2Gkl/Tnf^tm2Gkl Tnfrsf1a^tm1Blt/Tnfrsf1a^tm1Blt	involves: 129P2/OlaHsd * 129S/SvEv * C57BL/6	MGI:3622063
cx13	Tcrd^tm1Mom/Tcrd^tm1Mom Tnf^tm2Gkl/Tnf⁺	involves: 129P2/OlaHsd * 129S/SvEv * C57BL/6J	MGI:3629523
cx14	Mapkapk2^tm1Mgl/Mapkapk2^tm1Mgl Tnf^tm2Gkl/Tnf⁺	involves: 129P2/OlaHsd * 129S/SvEv * C57BL/6J	MGI:3629603
cx15	Map3k8^tm1Pnt/Map3k8^tm1Pnt Tnf^tm2Gkl/Tnf⁺	involves: 129P2/OlaHsd * 129S/SvEv * C57BL/6J	MGI:3629606
cx16	Mapk9^tm1Flv/Mapk9^tm1Flv Tnf^tm2Gkl/Tnf⁺	involves: 129P2/OlaHsd * 129S/SvEv * C57BL/6J	MGI:3629608
cx17	Cd44^tm1Hbg/Cd44⁺ Tnf^tm2Gkl/Tnf⁺	involves: 129S/SvEv * 129S1/Sv * 129X1/SvJ * C57BL/6	MGI:5702939
cx18	Cd44^tm1Hbg/Cd44^tm1Hbg Tnf^tm2Gkl/Tnf⁺	involves: 129S/SvEv * 129S1/Sv * 129X1/SvJ * C57BL/6	MGI:5702938
cx19	Il12b^tm1Jm/Il12b^tm1Jm Tnf^tm2Gkl/Tnf⁺	involves: 129S/SvEv * 129S1/Sv * C57BL/6J	MGI:3629590
cx20	Ccl25^tm1.1Mal/Ccl25^tm1.1Mal Tnf^tm2Gkl/Tnf⁺	involves: 129S/SvEv * 129S2/SvPas * C57BL/6	MGI:3799633
cx21	Tnf^tm2Gkl/Tnf⁺ Tnfrsf1b^tm1Mwm/Tnfrsf1b^tm1Mwm	involves: 129S/SvEv * 129S2/SvPas * C57BL/6	MGI:3622064
cx22	Ccr9^tm1.1Mal/Ccr9^tm1.1Mal Tnf^tm2Gkl/Tnf⁺	involves: 129S/SvEv * 129S2/SvPas * C57BL/6	MGI:3799634
cx23	Cd4^tm1Mak/Cd4^tm1Mak Tnf^tm2Gkl/Tnf⁺	involves: 129S/SvEv * 129S2/SvPas * C57BL/6J	MGI:3629516
cx24	B2m^tm1Jae/B2m^tm1Jae Tnf^tm2Gkl/Tnf⁺	involves: 129S/SvEv * 129S2/SvPas * C57BL/6J	MGI:3629515
cx25	Ighm^tm1Cgn/Ighm^tm1Cgn Tnf^tm2Gkl/Tnf⁺	involves: 129S/SvEv * 129S2/SvPas * C57BL/6J	MGI:3629519
cx26	Rag1^tm1Mom/Rag1^tm1Mom Tnf^tm2Gkl/Tnf⁺	involves: 129S/SvEv * 129S7/SvEvBrd * C57BL/6	MGI:3622066
cx27	Ifng^tm1Ts/Ifng^tm1Ts Tnf^tm2Gkl/Tnf⁺	involves: 129S/SvEv * 129S7/SvEvBrd * C57BL/6J	MGI:3629594
cx28	Itgb7^tm1Cgn/Itgb7^tm1Cgn Tnf^tm2Gkl/Tnf⁺	involves: 129S/SvEv * C57BL/6	MGI:3799636
cx29	Tnf^tm2Gkl/Tnf⁺ Tnfrsf1b^tm1.2Gkl/Tnfrsf1b^tm1.2Gkl	involves: 129S/SvEv * C57BL/6 * C57BL/6J	MGI:6195613

Allelic Composition	Tnf^tm2Gkl/Tnf^tm2Gkl
Genetic Background	involves: 129S/SvEv * C57BL/6

Find Mice

Using the International Mouse Strain Resource (IMSR)
Mouse lines carrying:
Tnf^tm2Gkl mutation (1 available); any Tnf mutation (46 available)

♀	phenotype observed in females
♂	phenotype observed in males
N	normal phenotype

mortality/aging

premature death ( J:54056 )

• die between 5 and 12 weeks of age

cardiovascular system

cardiovalvulitis ( J:226052 )

• inflammation of the heart valves

immune system

cardiovalvulitis ( J:226052 )

• inflammation of the heart valves

small intestinal inflammation ( J:54056 )

• first detected between 2 and 4 weeks of age as mucosal abnormalities with intestinal villous blunting and broadening generally confined to the terminal ileum

• becomes severe by 4 weeks, with increased numbers of submucosal lymphoid aggregates and follicles eventually penetrating deep into the muscular layers of the bowel wall

thymus hypoplasia ( J:54056 )

• severe hypoplasia with atrophy and disorganization of the cortical and medullary areas is seen at 4 weeks of age; however at 12 days of age the ratio of thymic and peripheral T cell subsets is normal

increased circulating tumor necrosis factor level ( J:54056 )

• at 6 weeks of age circulating levels of TNF are up to 822 +/- 447 pg/ml compared to undetectable levels in wild-type mice

rheumatoid arthritis ( J:54056 )

• develop signs of chronic polyarthritis including joint swelling, distortion of fore and hind paw morphology, impaired movement

• disease onset occurs at 12 days of age

• early signs include hyperplasia of the synovial membrane and the presence of polymorphonuclear infiltrates; progressing to pannus and fibrous tissue formation, subchondral bone erosion, and articular cartilage destruction

• both IgM and IgG are detected in arthritic joints

growth/size/body

decreased body weight ( J:54056 )

• body weight does no exceed 6-7 g

digestive/alimentary system

small intestinal inflammation ( J:54056 )

• first detected between 2 and 4 weeks of age as mucosal abnormalities with intestinal villous blunting and broadening generally confined to the terminal ileum

• becomes severe by 4 weeks, with increased numbers of submucosal lymphoid aggregates and follicles eventually penetrating deep into the muscular layers of the bowel wall

skeleton

rheumatoid arthritis ( J:54056 )

• develop signs of chronic polyarthritis including joint swelling, distortion of fore and hind paw morphology, impaired movement

• disease onset occurs at 12 days of age

• both IgM and IgG are detected in arthritic joints

hematopoietic system

thymus hypoplasia ( J:54056 )

homeostasis/metabolism

increased circulating tumor necrosis factor level ( J:54056 )

• at 6 weeks of age circulating levels of TNF are up to 822 +/- 447 pg/ml compared to undetectable levels in wild-type mice

endocrine/exocrine glands

thymus hypoplasia ( J:54056 )

Mouse Models of Human Disease	DO ID	OMIM ID(s)	Ref(s)
inflammatory bowel disease	DOID:0050589	OMIM:PS266600	J:54056
rheumatoid arthritis	DOID:7148	OMIM:180300	J:54056

Allelic Composition	Tnf^tm2Gkl/Tnf⁺
Genetic Background	B6.129S-Tnf^tm2Gkl/Jarn

Find Mice

Using the International Mouse Strain Resource (IMSR)
Mouse lines carrying:
Tnf^tm2Gkl mutation (1 available); any Tnf mutation (46 available)

♀	phenotype observed in females
♂	phenotype observed in males
N	normal phenotype

immune system

ileum inflammation ( J:131978 , J:145626 )

• antibody depletion of CD8+ T cells does not improve ileitis (J:131978)

• with increased levels of soluble hyaluronan (J:145626)

increased CD4-positive, alpha-beta T cell number ( J:145626 )

• increased percentage of CD4+/CD44^high T cells in populations from the spleen, mesenteric lymph nodes and lamina propria by 20 weeks of age

increased CD4-positive, alpha-beta memory T cell number ( J:145626 )

abnormal CD8-positive, alpha beta T cell morphology ( J:131978 )

• CD8+ population polarized into CD44^high/CD103^low and CD44^low/CD103^high subsets in mice with advanced disease

abnormal CD4-positive, alpha-beta T cell physiology ( J:145626 )

• increased reactivity and rolling flux fraction

increased interferon-gamma secretion ( J:131978 )

• in CD8+/CD44^high T cells

increased interleukin-2 secretion ( J:145626 )

• in CD4+/CD44^high T cells

increased tumor necrosis factor secretion ( J:145626 )

• in CD4+/CD44^high T cells

digestive/alimentary system

ileum inflammation ( J:131978 , J:145626 )

• antibody depletion of CD8+ T cells does not improve ileitis (J:131978)

• with increased levels of soluble hyaluronan (J:145626)

hematopoietic system

increased CD4-positive, alpha-beta T cell number ( J:145626 )

• increased percentage of CD4+/CD44^high T cells in populations from the spleen, mesenteric lymph nodes and lamina propria by 20 weeks of age

increased CD4-positive, alpha-beta memory T cell number ( J:145626 )

abnormal CD8-positive, alpha beta T cell morphology ( J:131978 )

• CD8+ population polarized into CD44^high/CD103^low and CD44^low/CD103^high subsets in mice with advanced disease

abnormal CD4-positive, alpha-beta T cell physiology ( J:145626 )

• increased reactivity and rolling flux fraction

Allelic Composition	Tnf^tm2Gkl/Tnf⁺
Genetic Background	involves: 129S/SvEv * C57BL/6

Find Mice

Using the International Mouse Strain Resource (IMSR)
Mouse lines carrying:
Tnf^tm2Gkl mutation (1 available); any Tnf mutation (46 available)

♀	phenotype observed in females
♂	phenotype observed in males
N	normal phenotype

immune system

intestinal inflammation ( J:136667 )

• elevated chronic and acute inflammatory indices

small intestinal inflammation ( J:54056 , J:92307 , J:204922 )

• first detected between 2 and 4 weeks of age as mucosal abnormalities with intestinal villous blunting and broadening generally confined to the terminal ileum (J:54056)

• becomes severe by 8 weeks, with increased numbers of submucosal lymphoid aggregates and follicles eventually penetrating deep into the muscular layers of the bowel wall (J:54056)

• by 4-7 months of age complete loss of villous structure and rudimental granulomata are seen (J:54056)

• at 9 months similar bowel inflammation extending into the mucosal layers and loss of crypt morphology is seen in mice on a mixed background with or without SPRET/Ei (J:92307)

• mutants on a high-fat diet develop accelerated onset of intestinal inflammation compared to wild-type mice (J:204922)

ileum inflammation ( J:204922 )

increased dendritic cell number ( J:204922 )

• mutants show higher numbers of CD11c+ dendritic cells in the ileal lamina propria when fed a high-fat diet compared to wild-type mice

abnormal T cell subpopulation ratio ( J:136667 )

• at 16 weeks of age, the CD8alpha alpha to CD8alpha beta ratio is significantly decreased in the lamina propria of the ileum

abnormal CD8-positive, alpha beta T cell morphology ( J:136667 )

• at 4 weeks of age, fewer CD8alpha alpha intraepithelial lymphocytes are present in the ileum

• however, no significant difference is seen in the number of CD8alpha beta intraepithelial lymphocytes

abnormal alpha-beta intraepithelial T cell morphology ( J:136667 )

• decrease in TCRalpha beta CD8alpha alpha and TCRalpha beta CD8alpha alpha CD4 numbers

abnormal T cell physiology ( J:136667 )

• increase in the number of TNF-producing cells in the lamina propria and intraepithelial lymphocyte subsets

abnormal CD4-positive, alpha-beta T cell physiology ( J:136667 )

• reduced expression of interferon gamma and increased expression of interleukin 17 and 10 in CD4+ lymphocytes in the lamina propria of the ileum

abnormal T-helper 17 cell physiology ( J:204922 )

• mutants show increased Th17-biased lymphocyte infiltration into the lamina propria of the ileum on a high-fat diet compared to wild-type mice

abnormal circulating chemokine level ( J:204922 )

• mutants exhibit increased plasma CCL20 levels on both a regular or high-fat diet compared to wild-type mice

increased circulating tumor necrosis factor level ( J:54056 , J:204922 )

• at 6 weeks of age circulating levels of TNF are up between 90 and 430 pg/ml compared to undetectable levels in wild-type mice (J:54056)

• TNF plasma levels are increased at 12 weeks of age in mutants compared to wild-type mice, however high-fat diet does not result in a further increase (J:204922)

decreased inflammatory response ( J:204922 )

• expression analysis indicates that mutants do not show adipose tissue inflammation when fed a high-fat diet as seen in wild-type mice

arthritis ( J:92307 , J:136667 )

• Background Sensitivity: at 9 months arthritis is severe enough to reduce mobility unlike in mice on a mixed background including SPRET/Ei (J:92307)

• at 9 months joints show extensive lymphocytic infiltration, thickening of the synovial lining, pannus formation, and abnormal ingrowth of the synovial lining (J:92307)

rheumatoid arthritis ( J:54056 )

digestive/alimentary system

steatorrhea ( J:204922 )

• mutants show elevated fecal energy content when fed a high-fat diet, suggesting steatorrhea, which is not seen in wild-type mice

abnormal intestine physiology ( J:204922 )

• mutants show increased intestinal permeability when fed a high-fat diet

intestinal inflammation ( J:136667 )

• elevated chronic and acute inflammatory indices

small intestinal inflammation ( J:54056 , J:92307 , J:204922 )

• first detected between 2 and 4 weeks of age as mucosal abnormalities with intestinal villous blunting and broadening generally confined to the terminal ileum (J:54056)

• becomes severe by 8 weeks, with increased numbers of submucosal lymphoid aggregates and follicles eventually penetrating deep into the muscular layers of the bowel wall (J:54056)

• by 4-7 months of age complete loss of villous structure and rudimental granulomata are seen (J:54056)

• at 9 months similar bowel inflammation extending into the mucosal layers and loss of crypt morphology is seen in mice on a mixed background with or without SPRET/Ei (J:92307)

• mutants on a high-fat diet develop accelerated onset of intestinal inflammation compared to wild-type mice (J:204922)

ileum inflammation ( J:204922 )

skeleton

arthritis ( J:92307 , J:136667 )

• Background Sensitivity: at 9 months arthritis is severe enough to reduce mobility unlike in mice on a mixed background including SPRET/Ei (J:92307)

• at 9 months joints show extensive lymphocytic infiltration, thickening of the synovial lining, pannus formation, and abnormal ingrowth of the synovial lining (J:92307)

rheumatoid arthritis ( J:54056 )

homeostasis/metabolism

steatorrhea ( J:204922 )

• mutants show elevated fecal energy content when fed a high-fat diet, suggesting steatorrhea, which is not seen in wild-type mice

decreased susceptibility to diet-induced obesity ( J:204922 )

• mutants do not develop obesity on a high-fat diet as seen in wild-type mice

• mutants on a high-fat diet do not show increased fat depots or enlarged adipocytes as seen in wild-type mice

abnormal circulating leptin level ( J:204922 )

• mutants on high-fat diet do not exhibit an increase in plasma leptin levels as seen in wild-type mice

abnormal circulating chemokine level ( J:204922 )

• mutants exhibit increased plasma CCL20 levels on both a regular or high-fat diet compared to wild-type mice

increased circulating tumor necrosis factor level ( J:54056 , J:204922 )

• at 6 weeks of age circulating levels of TNF are up between 90 and 430 pg/ml compared to undetectable levels in wild-type mice (J:54056)

• TNF plasma levels are increased at 12 weeks of age in mutants compared to wild-type mice, however high-fat diet does not result in a further increase (J:204922)

abnormal glucose homeostasis ( J:204922 )

• glucose homeostasis remains normal in mutants fed a high-fat diet unlike in wild-type mice which show impaired glucose tolerance and elevated fasting blood glucose

hematopoietic system

increased dendritic cell number ( J:204922 )

• mutants show higher numbers of CD11c+ dendritic cells in the ileal lamina propria when fed a high-fat diet compared to wild-type mice

abnormal T cell subpopulation ratio ( J:136667 )

• at 16 weeks of age, the CD8alpha alpha to CD8alpha beta ratio is significantly decreased in the lamina propria of the ileum

abnormal CD8-positive, alpha beta T cell morphology ( J:136667 )

• at 4 weeks of age, fewer CD8alpha alpha intraepithelial lymphocytes are present in the ileum

• however, no significant difference is seen in the number of CD8alpha beta intraepithelial lymphocytes

abnormal alpha-beta intraepithelial T cell morphology ( J:136667 )

• decrease in TCRalpha beta CD8alpha alpha and TCRalpha beta CD8alpha alpha CD4 numbers

abnormal T cell physiology ( J:136667 )

• increase in the number of TNF-producing cells in the lamina propria and intraepithelial lymphocyte subsets

abnormal CD4-positive, alpha-beta T cell physiology ( J:136667 )

• reduced expression of interferon gamma and increased expression of interleukin 17 and 10 in CD4+ lymphocytes in the lamina propria of the ileum

abnormal T-helper 17 cell physiology ( J:204922 )

• mutants show increased Th17-biased lymphocyte infiltration into the lamina propria of the ileum on a high-fat diet compared to wild-type mice

integument

alopecia ( J:92307 )

• at 9 months of age

behavior/neurological

abnormal food intake ( J:204922 )

• mutants exhibit increased energy intake on a high-fat diet

growth/size/body

decreased susceptibility to diet-induced obesity ( J:204922 )

• mutants do not develop obesity on a high-fat diet as seen in wild-type mice

• mutants on a high-fat diet do not show increased fat depots or enlarged adipocytes as seen in wild-type mice

Mouse Models of Human Disease	DO ID	OMIM ID(s)	Ref(s)
inflammatory bowel disease	DOID:0050589	OMIM:PS266600	J:136667 , J:204922 , J:54056
rheumatoid arthritis	DOID:7148	OMIM:180300	J:54056

Allelic Composition	Tnf^tm2Gkl/Tnf⁺
Genetic Background	involves: 129S/SvEv * C57BL/6 * CBA

Find Mice

Using the International Mouse Strain Resource (IMSR)
Mouse lines carrying:
Tnf^tm2Gkl mutation (1 available); any Tnf mutation (46 available)

♀	phenotype observed in females
♂	phenotype observed in males
N	normal phenotype

immune system

arthritis ( J:131930 )

• bilaterial inflammation of the sacroiliac joints occurs starting at 4 weeks of age

• the fibrocartilagenous portion of the joint is invaded by mononuclear cells that protrude into the bone marrow

skeleton

arthritis ( J:131930 )

• bilaterial inflammation of the sacroiliac joints occurs starting at 4 weeks of age

• the fibrocartilagenous portion of the joint is invaded by mononuclear cells that protrude into the bone marrow

Allelic Composition	Tnf^tm2Gkl/Tnf⁺
Genetic Background	involves: 129S/SvEv * C57BL/6J

Find Mice

Using the International Mouse Strain Resource (IMSR)
Mouse lines carrying:
Tnf^tm2Gkl mutation (1 available); any Tnf mutation (46 available)

♀	phenotype observed in females
♂	phenotype observed in males
N	normal phenotype

skeleton

abnormal joint morphology ( J:264147 )

• cultured synovial fibroblasts are bipolar rather than multipolar and exhibit a more complex and denser actin filament network

cellular

increased apoptosis ( J:108572 )

• mice display high levels of apoptosis in the ilea at 3 months of age

increased cell migration ( J:264147 )

• valvular interstitial cells show 70-80% closure of a wound in culture compared to around 20% in wild-type cells, indicating increased migration

increased fibroblast cell migration ( J:264147 )

• synovial fibroblasts show 70-80% closure of a wound in culture compared to around 20% in wild-type cells, indicating increased migration

increased cell proliferation ( J:264147 )

• valvular interstitial cells display a 2- to 3-fold increase in proliferation

increased fibroblast proliferation ( J:264147 )

• synovial fibroblasts display a 2- to 3-fold increase in proliferation

cardiovascular system

abnormal aorta bulb morphology ( J:264147 )

• by 16 weeks of age, the aortic root is thickened to about 10-15 times compared with wild-type

abnormal aortic valve morphology ( J:264147 )

• cultured valvular interstitial cells are bipolar rather than multipolar and exhibit a more complex and denser actin filament network

thick aortic valve cusps ( J:264147 )

• by 16 weeks of age, the aortic valve leaflets are thickened to about 10-15 times compared with wild-type

aortic valve stenosis ( J:264147 )

• mice progressively develop stenosis of the aortic valve leaflets starting at 8 weeks of age with 100% incidence

• treatment with an anti-TNF, etanercept (enbrel), and prophylactic regimen for 10 weeks upon disease initiation prevents the development of aortic valve stenosis and fibrosis

cardiac fibrosis ( J:264147 )

• thickened valves develop fibrosis but show very little immune cell infiltration

• treatment with an anti-TNF, etanercept (enbrel), and prophylactic regimen for 10 weeks upon disease initiation prevents the development of aortic valve fibrosis

decreased cardiac output ( J:264147 )

• cardiac output is reduced at 4 months of age

decreased ventricle muscle contractility ( J:264147 )

• mice exhibit a mild, but significant, reduction in left ventricular ejection fraction

abnormal aortic valve flow ( J:264147 )

• mice exhibit a higher peak aortic valve flow

decreased heart rate ( J:264147 )

• heart rate is reduced at 4 months of age

prolonged QT interval ( J:264147 )

• mice exhibit prolonged heart rate corrected time from the start of the Q wave to the end of the T wave on the ECG trace (QTc) interval prolongation

homeostasis/metabolism

increased circulating tumor necrosis factor level ( J:264147 )

• circulating TNF levels are elevated

enhanced wound healing ( J:264147 )

• synovial fibroblasts and valvular interstitial cells show 70-80% closure of a wound in culture compared to around 20% in wild-type cells

immune system

small intestinal inflammation ( J:108572 )

• inflammatory bowel disease develops between 4-8 weeks of age

enlarged spleen ( J:108572 )

• mild splenomegaly development correlates with inflammatory bowel disease (IBD) development and becomes significant by 4 months of age

abnormal myelopoiesis ( J:108572 )

• splenocyte counts past 2 months of age show increases in CD11b+ myeloid cells

increased CD8-positive, alpha-beta T cell number ( J:108572 )

• there is a significant increase in CD8+ T cell number in Tnf^tm2Gkl mice past 2 months of age

abnormal cytotoxic T cell physiology ( J:108572 )

• T lymphocytes show a high degree of target cell lysis of syngeneic targets

• in allogeneic mixed lymphocyte reactions, splenocytes show enhanced proliferation compared to wild-type controls

increased circulating tumor necrosis factor level ( J:264147 )

• circulating TNF levels are elevated

increased tumor necrosis factor secretion ( J:264147 )

• levels of secreted TNF-alpha in supernatants of cultured synovial fibroblasts and valvular interstitial cells are elevated

abnormal response to transplant ( J:108572 )

• when lethality irradiated heterozygotes (that had also received anti-Tnf antibody treatment) receive bone marrow from wild-type mice only display mild villus blunting 9 weeks after removal of antibody treatment

hematopoietic system

enlarged spleen ( J:108572 )

• mild splenomegaly development correlates with inflammatory bowel disease (IBD) development and becomes significant by 4 months of age

abnormal myelopoiesis ( J:108572 )

• splenocyte counts past 2 months of age show increases in CD11b+ myeloid cells

increased CD8-positive, alpha-beta T cell number ( J:108572 )

• there is a significant increase in CD8+ T cell number in Tnf^tm2Gkl mice past 2 months of age

abnormal cytotoxic T cell physiology ( J:108572 )

• T lymphocytes show a high degree of target cell lysis of syngeneic targets

• in allogeneic mixed lymphocyte reactions, splenocytes show enhanced proliferation compared to wild-type controls

muscle

decreased ventricle muscle contractility ( J:264147 )

• mice exhibit a mild, but significant, reduction in left ventricular ejection fraction

digestive/alimentary system

small intestinal inflammation ( J:108572 )

• inflammatory bowel disease develops between 4-8 weeks of age

growth/size/body

enlarged spleen ( J:108572 )

• mild splenomegaly development correlates with inflammatory bowel disease (IBD) development and becomes significant by 4 months of age

Mouse Models of Human Disease	DO ID	OMIM ID(s)	Ref(s)
aortic valve stenosis	DOID:1712		J:264147
rheumatoid arthritis	DOID:7148	OMIM:180300	J:264147
spondyloarthropathy	DOID:1123		J:264147

Allelic Composition	Tnf^tm2Gkl/Tnf⁺
Genetic Background	involves: 129S/SvEv * C57BL/6 * SPRET/Ei

Find Mice

Using the International Mouse Strain Resource (IMSR)
Mouse lines carrying:
Tnf^tm2Gkl mutation (1 available); any Tnf mutation (46 available)

♀	phenotype observed in females
♂	phenotype observed in males
N	normal phenotype

immune system

small intestinal inflammation ( J:92307 )

• at 9 months similar bowel inflammation extending into the mucosal layers and loss of crypt morphology is seen in mice on a mixed background with or without SPRET/Ei

arthritis ( J:92307 )

• Background Sensitivity: at 9 months arthritis is not severe enough to reduce mobility unlike in mice on a mixed background that does not include SPRET/Ei

digestive/alimentary system

small intestinal inflammation ( J:92307 )

• at 9 months similar bowel inflammation extending into the mucosal layers and loss of crypt morphology is seen in mice on a mixed background with or without SPRET/Ei

skeleton

arthritis ( J:92307 )

• Background Sensitivity: at 9 months arthritis is not severe enough to reduce mobility unlike in mice on a mixed background that does not include SPRET/Ei

integument

alopecia ( J:92307 )

• at 9 months of age

Allelic Composition	Tnf^tm1Gkl/Tnf^tm2Gkl
Genetic Background	involves: 129S/SvEv * C57BL/6

Find Mice

Using the International Mouse Strain Resource (IMSR)
Mouse lines carrying:
Tnf^tm1Gkl mutation (6 available); any Tnf mutation (46 available)
Tnf^tm2Gkl mutation (1 available); any Tnf mutation (46 available)

♀	phenotype observed in females
♂	phenotype observed in males
N	normal phenotype

immune system

increased circulating tumor necrosis factor level ( J:54056 )

• at 6 weeks of age circulating levels of TNF are up between 90 and 430 pg/ml compared to undetectable levels in wild-type mice

increased tumor necrosis factor secretion ( J:54056 )

• increased basal and LPS-induced secretion of TNF from thioglycollate-elicited peritoneal macrophages and bone marrow-derived macrophages

• spleen derived T lymphocytes have 3-fold greater TNF production and prolonged mRNA accumulation after incubation with an agonistic anti-CD3 antibody

• splenic B220+ cells also show increased basal and mitogen-stimulated TNF production

• primary synovial and lung fibroblasts display spontaneous TNF secretion and increased secretion following LPS stimulation unlike controls

rheumatoid arthritis ( J:54056 )

• disease onset occurs at 6-8 weeks of age

• both IgM and IgG are detected in arthritic joints

increased susceptibility to endotoxin shock ( J:54056 )

• increased sensitivity to LPS-induced mortality with 5 of 10 dying after injection of 100 ug/ 25 g compared to complete survival of control mice at the same dose

skeleton

rheumatoid arthritis ( J:54056 )

• disease onset occurs at 6-8 weeks of age

• both IgM and IgG are detected in arthritic joints

homeostasis/metabolism

increased circulating tumor necrosis factor level ( J:54056 )

• at 6 weeks of age circulating levels of TNF are up between 90 and 430 pg/ml compared to undetectable levels in wild-type mice

Mouse Models of Human Disease	DO ID	OMIM ID(s)	Ref(s)
inflammatory bowel disease	DOID:0050589	OMIM:PS266600	J:54056
rheumatoid arthritis	DOID:7148	OMIM:180300	J:54056

Allelic Composition	Tnf^tm2Gkl/Tnf⁺ Tnfrsf1b^tm1.1Gkl/Tnfrsf1b^tm1.1Gkl Tg(Col6a1-cre)1Gkl/0
Genetic Background	involves: 129S/SvEv * C57BL/6 * C57BL/6J * CBA

Find Mice

Using the International Mouse Strain Resource (IMSR)
Mouse lines carrying:
Tg(Col6a1-cre)1Gkl mutation (1 available)
Tnfrsf1b^tm1.1Gkl mutation (0 available); any Tnfrsf1b mutation (41 available)
Tnf^tm2Gkl mutation (1 available); any Tnf mutation (46 available)

♀	phenotype observed in females
♂	phenotype observed in males
N	normal phenotype

cardiovascular system

cardiovascular system phenotype ( J:264147 )

N	• mice show amelioration of the aortic valve stenosis seen in single Tnf^tm2Gkl heterozygotes, including a decrease of the leaflets surface area and reduction of fibrosis

skeleton

joint inflammation ( J:264147 )

• mice show reduced clinical features of arthritis compared to single Tnf^tm2Gkl heterozygotes, with a reduction of pannus formation and cartilage/bone destruction

cellular

abnormal cell physiology ( J:264147 )

• valvular interstitial cells fail to become activated

• however, cultured valvular interstitial cells appear similar to wild-type cells and exhibit normal proliferation

abnormal cell adhesion ( J:264147 )

• synovial fibroblast and valvular interstitial cell adhesion to a fibronectin substrate is reduced by almost 50% compared to the levels in single Tnf^tm2Gkl heterozygotes but is somewhat higher than in wild-type cells

abnormal fibroblast physiology ( J:264147 )

• synovial fibroblasts fail to become activated

• however, cultured synovial fibroblasts appear similar to wild-type cells and exhibit normal proliferation

homeostasis/metabolism

increased circulating tumor necrosis factor level ( J:264147 )

• circulating TNF levels are elevated

abnormal wound healing ( J:264147 )

• synovial fibroblasts and valvular interstitial cells show only 40-45% closure of a wound in culture compared to 70-80% closure in single Tnf^tm2Gkl heterozygotes and about 20% in wild-type cells

immune system

increased circulating tumor necrosis factor level ( J:264147 )

• circulating TNF levels are elevated

increased tumor necrosis factor secretion ( J:264147 )

• levels of secreted TNF-alpha in supernatants of cultured synovial fibroblasts and valvular interstitial cells are elevated

joint inflammation ( J:264147 )

• mice show reduced clinical features of arthritis compared to single Tnf^tm2Gkl heterozygotes, with a reduction of pannus formation and cartilage/bone destruction

Allelic Composition	Tnf^tm2Gkl/Tnf⁺ Tnfrsf1a^tm2Gkl/Tnfrsf1a^tm2Gkl Tg(Col6a1-cre)1Gkl/0
Genetic Background	involves: 129S/SvEv * C57BL/6 * C57BL/6J * CBA

Find Mice

Using the International Mouse Strain Resource (IMSR)
Mouse lines carrying:
Tg(Col6a1-cre)1Gkl mutation (1 available)
Tnfrsf1a^tm2Gkl mutation (1 available); any Tnfrsf1a mutation (47 available)
Tnf^tm2Gkl mutation (1 available); any Tnf mutation (46 available)

♀	phenotype observed in females
♂	phenotype observed in males
N	normal phenotype

cardiovascular system

cardiovascular system phenotype ( J:264147 )

N	• aortic valves appear normal at 16 weeks of age, showing no signs of disease

Allelic Composition	Tnf^tm2Gkl/Tnf⁺ Tnfrsf1a^tm2Gkl/Tnfrsf1a^tm2Gkl Tg(Col6a1-cre)1Gkl/?
Genetic Background	involves: 129S/SvEv * C57BL/6 * CBA

Find Mice

♀	phenotype observed in females
♂	phenotype observed in males
N	normal phenotype

digestive/alimentary system

small intestinal inflammation ( J:131930 )

• the ileum contains inflammatory pathology reminiscent of Crohn's disease

• pathology includes blunting of intestinal villi, and infiltration of inflammation cells into the mucosal and submucosal layers

• 100% of mice have disease by 8 weeks of age

immune system

small intestinal inflammation ( J:131930 )

• the ileum contains inflammatory pathology reminiscent of Crohn's disease

• pathology includes blunting of intestinal villi, and infiltration of inflammation cells into the mucosal and submucosal layers

• 100% of mice have disease by 8 weeks of age

arthritis ( J:131930 )

• 100% of mice have arthritis by 8 weeks of age

• joints are infiltrated by mononuclear cells

• mice also develop spondyloarthritis in their sacroiliac joints

skeleton

arthritis ( J:131930 )

• 100% of mice have arthritis by 8 weeks of age

• joints are infiltrated by mononuclear cells

• mice also develop spondyloarthritis in their sacroiliac joints

Allelic Composition	Mapk11^tm1Jsca/Mapk11^tm1Jsca Tnf^tm2Gkl/Tnf⁺
Genetic Background	involves: 129P2/OlaHsd * 129S/SvEv * C57BL/6

Find Mice

Using the International Mouse Strain Resource (IMSR)
Mouse lines carrying:
Mapk11^tm1Jsca mutation (0 available); any Mapk11 mutation (35 available)
Tnf^tm2Gkl mutation (1 available); any Tnf mutation (46 available)

♀	phenotype observed in females
♂	phenotype observed in males
N	normal phenotype

immune system

ileum inflammation ( J:107771 )

• onset and severity of inflammation of the terminal ileum are similar to mice heterozygous for the Tnf allele only

arthritis ( J:107771 )

• onset and severity of arthritis are similar to mice heterozygous for the Tnf allele only

digestive/alimentary system

ileum inflammation ( J:107771 )

• onset and severity of inflammation of the terminal ileum are similar to mice heterozygous for the Tnf allele only

skeleton

arthritis ( J:107771 )

• onset and severity of arthritis are similar to mice heterozygous for the Tnf allele only

Allelic Composition	Tnf^tm2Gkl/Tnf^tm2Gkl Tnfrsf1a^tm1Blt/Tnfrsf1a^tm1Blt
Genetic Background	involves: 129P2/OlaHsd * 129S/SvEv * C57BL/6

Find Mice

Using the International Mouse Strain Resource (IMSR)
Mouse lines carrying:
Tnfrsf1a^tm1Blt mutation (6 available); any Tnfrsf1a mutation (47 available)
Tnf^tm2Gkl mutation (1 available); any Tnf mutation (46 available)

♀	phenotype observed in females
♂	phenotype observed in males
N	normal phenotype

immune system

increased circulating tumor necrosis factor level ( J:54056 )

• at 6 weeks of age circulating levels of TNF are 320 +/- 160 pg/ml in disease free mutants compared to undetectable levels in wild-type mice

• however, no signs of arthritis or inflammatory bowel disease are detected

increased tumor necrosis factor secretion ( J:54056 )

• increased basal and LPS-induced secretion of TNF from thioglycollate-elicited peritoneal macrophages and bone marrow-derived macrophages

• primary synovial and lung fibroblasts display spontaneous TNF secretion and increased secretion following LPS stimulation unlike controls

homeostasis/metabolism

increased circulating tumor necrosis factor level ( J:54056 )

• at 6 weeks of age circulating levels of TNF are 320 +/- 160 pg/ml in disease free mutants compared to undetectable levels in wild-type mice

• however, no signs of arthritis or inflammatory bowel disease are detected

Allelic Composition	Tcrd^tm1Mom/Tcrd^tm1Mom Tnf^tm2Gkl/Tnf⁺
Genetic Background	involves: 129P2/OlaHsd * 129S/SvEv * C57BL/6J

Find Mice

Using the International Mouse Strain Resource (IMSR)
Mouse lines carrying:
Tcrd^tm1Mom mutation (13 available); any Tcrd mutation (15 available)
Tnf^tm2Gkl mutation (1 available); any Tnf mutation (46 available)

♀	phenotype observed in females
♂	phenotype observed in males
N	normal phenotype

immune system

small intestinal inflammation ( J:108572 )

• development and severity of inflammatory bowel disease are similar to Tnf^tm2Gkl/+, wild-type B2m controls

digestive/alimentary system

small intestinal inflammation ( J:108572 )

• development and severity of inflammatory bowel disease are similar to Tnf^tm2Gkl/+, wild-type B2m controls

Allelic Composition	Mapkapk2^tm1Mgl/Mapkapk2^tm1Mgl Tnf^tm2Gkl/Tnf⁺
Genetic Background	involves: 129P2/OlaHsd * 129S/SvEv * C57BL/6J

Find Mice

Using the International Mouse Strain Resource (IMSR)
Mouse lines carrying:
Mapkapk2^tm1Mgl mutation (0 available); any Mapkapk2 mutation (36 available)
Tnf^tm2Gkl mutation (1 available); any Tnf mutation (46 available)

♀	phenotype observed in females
♂	phenotype observed in males
N	normal phenotype

mortality/aging

premature death ( J:108572 )

• increase in mortality from 8 weeks of age onward

cellular

decreased apoptosis ( J:108572 )

• mice have fewer apoptotic cells in inflamed ileal tissue compared to Tnf^tm2Gkl/+ controls

immune system

immune system phenotype ( J:108572 )

N	• there is no change in CD4+ to CD8+ ratios compared to findings in Tnf^tm2Gkl/+ single mutants

small intestinal inflammation ( J:108572 )

• Tnf^tm2Gkl phenotype is exacerbated in these mice

granulomatous inflammation ( J:108572 )

• IBD is associated with early formation of multiple granulomas

digestive/alimentary system

small intestinal inflammation ( J:108572 )

• Tnf^tm2Gkl phenotype is exacerbated in these mice

Allelic Composition	Map3k8^tm1Pnt/Map3k8^tm1Pnt Tnf^tm2Gkl/Tnf⁺
Genetic Background	involves: 129P2/OlaHsd * 129S/SvEv * C57BL/6J

Find Mice

Using the International Mouse Strain Resource (IMSR)
Mouse lines carrying:
Map3k8^tm1Pnt mutation (0 available); any Map3k8 mutation (41 available)
Tnf^tm2Gkl mutation (1 available); any Tnf mutation (46 available)

♀	phenotype observed in females
♂	phenotype observed in males
N	normal phenotype

immune system

small intestinal inflammation ( J:108572 )

• there is a delayed onset and significant attenuation of disease compared to controls

increased CD8-positive, alpha-beta T cell number ( J:108572 )

• number of CD8+CD44^hi T cells is higher than in Tnf^tm2Gkl/+ controls

increased single-positive T cell number ( J:108572 )

• there is a significant increase in numbers of CD4+ and CD8+ cells

hematopoietic system

increased CD8-positive, alpha-beta T cell number ( J:108572 )

• number of CD8+CD44^hi T cells is higher than in Tnf^tm2Gkl/+ controls

increased single-positive T cell number ( J:108572 )

• there is a significant increase in numbers of CD4+ and CD8+ cells

digestive/alimentary system

small intestinal inflammation ( J:108572 )

• there is a delayed onset and significant attenuation of disease compared to controls

Allelic Composition	Mapk9^tm1Flv/Mapk9^tm1Flv Tnf^tm2Gkl/Tnf⁺
Genetic Background	involves: 129P2/OlaHsd * 129S/SvEv * C57BL/6J

Find Mice

Using the International Mouse Strain Resource (IMSR)
Mouse lines carrying:
Mapk9^tm1Flv mutation (2 available); any Mapk9 mutation (33 available)
Tnf^tm2Gkl mutation (1 available); any Tnf mutation (46 available)

♀	phenotype observed in females
♂	phenotype observed in males
N	normal phenotype

cellular

increased apoptosis ( J:108572 )

• mice have significantly higher numbers of apoptotic cells in the ilea compared to lower numbers in the infiltrate indicating a higher rate of apoptosis

immune system

immune system phenotype ( J:108572 )

N	• there is no change in CD4+ to CD8+ ratios compared to findings in Tnf^tm2Gkl/+ single mutants

small intestinal inflammation ( J:108572 )

• there is a delayed onset and significant attenuation of disease

digestive/alimentary system

small intestinal inflammation ( J:108572 )

• there is a delayed onset and significant attenuation of disease

Allelic Composition	Cd44^tm1Hbg/Cd44⁺ Tnf^tm2Gkl/Tnf⁺
Genetic Background	involves: 129S/SvEv * 129S1/Sv * 129X1/SvJ * C57BL/6

Find Mice

Using the International Mouse Strain Resource (IMSR)
Mouse lines carrying:
Cd44^tm1Hbg mutation (4 available); any Cd44 mutation (67 available)
Tnf^tm2Gkl mutation (1 available); any Tnf mutation (46 available)

♀	phenotype observed in females
♂	phenotype observed in males
N	normal phenotype

digestive/alimentary system

ileum inflammation ( J:145626 )

• reduced ileitis compared with Tnf^tm2Gkl heterozygous mice

immune system

ileum inflammation ( J:145626 )

• reduced ileitis compared with Tnf^tm2Gkl heterozygous mice

Allelic Composition	Cd44^tm1Hbg/Cd44^tm1Hbg Tnf^tm2Gkl/Tnf⁺
Genetic Background	involves: 129S/SvEv * 129S1/Sv * 129X1/SvJ * C57BL/6

Find Mice

♀	phenotype observed in females
♂	phenotype observed in males
N	normal phenotype

digestive/alimentary system

digestive/alimentary phenotype ( J:145626 )

N	• mice exhibit attenuation of ileitis

immune system

immune system phenotype ( J:145626 )

N	• mice exhibit attenuation of ileitis

Allelic Composition	Il12b^tm1Jm/Il12b^tm1Jm Tnf^tm2Gkl/Tnf⁺
Genetic Background	involves: 129S/SvEv * 129S1/Sv * C57BL/6J

Find Mice

Using the International Mouse Strain Resource (IMSR)
Mouse lines carrying:
Il12b^tm1Jm mutation (4 available); any Il12b mutation (31 available)
Tnf^tm2Gkl mutation (1 available); any Tnf mutation (46 available)

♀	phenotype observed in females
♂	phenotype observed in males
N	normal phenotype

immune system

small intestinal inflammation ( J:108572 )

• mice display delayed development and attenuation of inflammatory bowel disease

digestive/alimentary system

small intestinal inflammation ( J:108572 )

• mice display delayed development and attenuation of inflammatory bowel disease

Allelic Composition	Ccl25^tm1.1Mal/Ccl25^tm1.1Mal Tnf^tm2Gkl/Tnf⁺
Genetic Background	involves: 129S/SvEv * 129S2/SvPas * C57BL/6

Find Mice

Using the International Mouse Strain Resource (IMSR)
Mouse lines carrying:
Ccl25^tm1.1Mal mutation (1 available); any Ccl25 mutation (39 available)
Tnf^tm2Gkl mutation (1 available); any Tnf mutation (46 available)

♀	phenotype observed in females
♂	phenotype observed in males
N	normal phenotype

immune system

intestinal inflammation ( J:136667 )

• develop inflammatory bowl disease with similar onset, progression, and severity as in littermates heterozygous for both alleles

• elevated acute and chronic inflammatory indices similar to littermates heterozygous for both alleles

abnormal T cell subpopulation ratio ( J:136667 )

• decrease in the CD8alpha alpha to CD8alpha beta ratio similar to that in mice heterozygous for Tnf^tm2Gkl alone

decreased gamma-delta intraepithelial T cell number ( J:136667 )

• more pronounced decrease in this subset early in the inflammatory disease process compared to mice heterozygous for Tnf^tm2Gkl alone

abnormal alpha-beta intraepithelial T cell morphology ( J:136667 )

• decrease in TCRalpha beta CD8alpha alpha and TCRalpha beta CD8alpha alpha CD4 numbers similar to mice heterozygous for Tnf^tm2Gkl alone

digestive/alimentary system

intestinal inflammation ( J:136667 )

• develop inflammatory bowl disease with similar onset, progression, and severity as in littermates heterozygous for both alleles

• elevated acute and chronic inflammatory indices similar to littermates heterozygous for both alleles

hematopoietic system

abnormal T cell subpopulation ratio ( J:136667 )

• decrease in the CD8alpha alpha to CD8alpha beta ratio similar to that in mice heterozygous for Tnf^tm2Gkl alone

decreased gamma-delta intraepithelial T cell number ( J:136667 )

• more pronounced decrease in this subset early in the inflammatory disease process compared to mice heterozygous for Tnf^tm2Gkl alone

abnormal alpha-beta intraepithelial T cell morphology ( J:136667 )

• decrease in TCRalpha beta CD8alpha alpha and TCRalpha beta CD8alpha alpha CD4 numbers similar to mice heterozygous for Tnf^tm2Gkl alone

Allelic Composition	Tnf^tm2Gkl/Tnf⁺ Tnfrsf1b^tm1Mwm/Tnfrsf1b^tm1Mwm
Genetic Background	involves: 129S/SvEv * 129S2/SvPas * C57BL/6

Find Mice

Using the International Mouse Strain Resource (IMSR)
Mouse lines carrying:
Tnfrsf1b^tm1Mwm mutation (2 available); any Tnfrsf1b mutation (41 available)
Tnf^tm2Gkl mutation (1 available); any Tnf mutation (46 available)

♀	phenotype observed in females
♂	phenotype observed in males
N	normal phenotype

immune system

small intestinal inflammation ( J:54056 )

• at 1-5 months of age, only mild intestinal inflammation and no signs of transmural inflammation are seen, unlike in mice heterozygous for Tnf^tm2Gkl only

rheumatoid arthritis ( J:54056 )

• arthritis is more aggressive and destructive than in mice heterozygous for Tnf^tm2Gkl only with increased swelling of the joints, synovial hyperplasia, numbers of polymorphonuclear infiltrates, and destruction of bone and cartilage

digestive/alimentary system

small intestinal inflammation ( J:54056 )

• at 1-5 months of age, only mild intestinal inflammation and no signs of transmural inflammation are seen, unlike in mice heterozygous for Tnf^tm2Gkl only

skeleton

rheumatoid arthritis ( J:54056 )

Allelic Composition	Ccr9^tm1.1Mal/Ccr9^tm1.1Mal Tnf^tm2Gkl/Tnf⁺
Genetic Background	involves: 129S/SvEv * 129S2/SvPas * C57BL/6

Find Mice

Using the International Mouse Strain Resource (IMSR)
Mouse lines carrying:
Ccr9^tm1.1Mal mutation (0 available); any Ccr9 mutation (27 available)
Tnf^tm2Gkl mutation (1 available); any Tnf mutation (46 available)

♀	phenotype observed in females
♂	phenotype observed in males
N	normal phenotype

immune system

intestinal inflammation ( J:136667 )

• develop inflammatory bowl disease with similar onset, progression, and severity as in littermates heterozygous for both alleles

• elevated acute and chronic inflammatory indices similar to littermates heterozygous for both alleles

abnormal T cell subpopulation ratio ( J:136667 )

• decrease in the CD8alpha alpha to CD8alpha beta ratio similar to that in mice heterozygous for Tnf^tm2Gkl alone

decreased gamma-delta intraepithelial T cell number ( J:136667 )

• more pronounced decrease in this subset early in the inflammatory disease process compared to mice heterozygous for Tnf^tm2Gkl alone

abnormal alpha-beta intraepithelial T cell morphology ( J:136667 )

• decrease in TCRalpha beta CD8alpha alpha and TCRalpha beta CD8alpha alpha CD4 numbers similar to mice heterozygous for Tnf^tm2Gkl alone

digestive/alimentary system

intestinal inflammation ( J:136667 )

• develop inflammatory bowl disease with similar onset, progression, and severity as in littermates heterozygous for both alleles

• elevated acute and chronic inflammatory indices similar to littermates heterozygous for both alleles

hematopoietic system

abnormal T cell subpopulation ratio ( J:136667 )

• decrease in the CD8alpha alpha to CD8alpha beta ratio similar to that in mice heterozygous for Tnf^tm2Gkl alone

decreased gamma-delta intraepithelial T cell number ( J:136667 )

• more pronounced decrease in this subset early in the inflammatory disease process compared to mice heterozygous for Tnf^tm2Gkl alone

abnormal alpha-beta intraepithelial T cell morphology ( J:136667 )

• decrease in TCRalpha beta CD8alpha alpha and TCRalpha beta CD8alpha alpha CD4 numbers similar to mice heterozygous for Tnf^tm2Gkl alone

Allelic Composition	Cd4^tm1Mak/Cd4^tm1Mak Tnf^tm2Gkl/Tnf⁺
Genetic Background	involves: 129S/SvEv * 129S2/SvPas * C57BL/6J

Find Mice

Using the International Mouse Strain Resource (IMSR)
Mouse lines carrying:
Cd4^tm1Mak mutation (5 available); any Cd4 mutation (82 available)
Tnf^tm2Gkl mutation (1 available); any Tnf mutation (46 available)

♀	phenotype observed in females
♂	phenotype observed in males
N	normal phenotype

mortality/aging

premature death ( J:108572 )

• there is high incidence of mortality in mice by age of 2-3 months

immune system

small intestinal inflammation ( J:108572 )

• mice show exacerbation of IBD compared to Tnf^tm2Gkl/+ mice

digestive/alimentary system

small intestinal inflammation ( J:108572 )

• mice show exacerbation of IBD compared to Tnf^tm2Gkl/+ mice

Allelic Composition	B2m^tm1Jae/B2m^tm1Jae Tnf^tm2Gkl/Tnf⁺
Genetic Background	involves: 129S/SvEv * 129S2/SvPas * C57BL/6J

Find Mice

Using the International Mouse Strain Resource (IMSR)
Mouse lines carrying:
B2m^tm1Jae mutation (8 available); any B2m mutation (122 available)
Tnf^tm2Gkl mutation (1 available); any Tnf mutation (46 available)

♀	phenotype observed in females
♂	phenotype observed in males
N	normal phenotype

immune system

small intestinal inflammation ( J:108572 )

• mice display delayed development and attenuation of inflammatory bowel disease

digestive/alimentary system

small intestinal inflammation ( J:108572 )

• mice display delayed development and attenuation of inflammatory bowel disease

Allelic Composition	Ighm^tm1Cgn/Ighm^tm1Cgn Tnf^tm2Gkl/Tnf⁺
Genetic Background	involves: 129S/SvEv * 129S2/SvPas * C57BL/6J

Find Mice

Using the International Mouse Strain Resource (IMSR)
Mouse lines carrying:
Ighm^tm1Cgn mutation (17 available); any Ighm mutation (55 available)
Tnf^tm2Gkl mutation (1 available); any Tnf mutation (46 available)

♀	phenotype observed in females
♂	phenotype observed in males
N	normal phenotype

immune system

small intestinal inflammation ( J:108572 )

• development and severity of inflammatory bowel disease are similar to Tnf^tm2Gkl/+, wild-type B2m controls

digestive/alimentary system

small intestinal inflammation ( J:108572 )

• development and severity of inflammatory bowel disease are similar to Tnf^tm2Gkl/+, wild-type B2m controls

Allelic Composition	Rag1^tm1Mom/Rag1^tm1Mom Tnf^tm2Gkl/Tnf⁺
Genetic Background	involves: 129S/SvEv * 129S7/SvEvBrd * C57BL/6

Find Mice

Using the International Mouse Strain Resource (IMSR)
Mouse lines carrying:
Rag1^tm1Mom mutation (49 available); any Rag1 mutation (120 available)
Tnf^tm2Gkl mutation (1 available); any Tnf mutation (46 available)

♀	phenotype observed in females
♂	phenotype observed in males
N	normal phenotype

immune system

small intestinal inflammation ( J:54056 )

• only minimal intestinal inflammation is seen, unlike in mice heterozygous for Tnf^tm2Gkl only

rheumatoid arthritis ( J:54056 )

• arthritis is similar to mice heterozygous for Tnf^tm2Gkl only

digestive/alimentary system

small intestinal inflammation ( J:54056 )

• only minimal intestinal inflammation is seen, unlike in mice heterozygous for Tnf^tm2Gkl only

skeleton

rheumatoid arthritis ( J:54056 )

• arthritis is similar to mice heterozygous for Tnf^tm2Gkl only

Allelic Composition	Ifng^tm1Ts/Ifng^tm1Ts Tnf^tm2Gkl/Tnf⁺
Genetic Background	involves: 129S/SvEv * 129S7/SvEvBrd * C57BL/6J

Find Mice

Using the International Mouse Strain Resource (IMSR)
Mouse lines carrying:
Ifng^tm1Ts mutation (18 available); any Ifng mutation (47 available)
Tnf^tm2Gkl mutation (1 available); any Tnf mutation (46 available)

♀	phenotype observed in females
♂	phenotype observed in males
N	normal phenotype

immune system

small intestinal inflammation ( J:108572 )

• development and severity of IBD are similar to Tnf^tm2Gkl/+, wild-type Ifng controls

digestive/alimentary system

small intestinal inflammation ( J:108572 )

• development and severity of IBD are similar to Tnf^tm2Gkl/+, wild-type Ifng controls

Allelic Composition	Itgb7^tm1Cgn/Itgb7^tm1Cgn Tnf^tm2Gkl/Tnf⁺
Genetic Background	involves: 129S/SvEv * C57BL/6

Find Mice

Using the International Mouse Strain Resource (IMSR)
Mouse lines carrying:
Itgb7^tm1Cgn mutation (3 available); any Itgb7 mutation (72 available)
Tnf^tm2Gkl mutation (1 available); any Tnf mutation (46 available)

♀	phenotype observed in females
♂	phenotype observed in males
N	normal phenotype

immune system

abnormal inflammatory response ( J:136667 )

• significant attenuation of the inflammatory bowel disease pathology with reduced acute and chronic inflammatory indices relative to mice heterozygous for Tnf^tm2Gkl alone

arthritis ( J:136667 )

• chronic inflammatory arthritis is similar to mice heterozygous for Tnf^tm2Gkl alone

skeleton

arthritis ( J:136667 )

• chronic inflammatory arthritis is similar to mice heterozygous for Tnf^tm2Gkl alone

Allelic Composition	Tnf^tm2Gkl/Tnf⁺ Tnfrsf1b^tm1.2Gkl/Tnfrsf1b^tm1.2Gkl
Genetic Background	involves: 129S/SvEv * C57BL/6 * C57BL/6J

Find Mice

Using the International Mouse Strain Resource (IMSR)
Mouse lines carrying:
Tnfrsf1b^tm1.2Gkl mutation (0 available); any Tnfrsf1b mutation (41 available)
Tnf^tm2Gkl mutation (1 available); any Tnf mutation (46 available)

♀	phenotype observed in females
♂	phenotype observed in males
N	normal phenotype

cardiovascular system

aortic valve stenosis ( J:264147 )

• mice exhibit an exacerbated aortic valve stenosis than seen in single Tnf^tm2Gkl heterozygotes, with an increase of valve leaflet surface area and fibrosis

• disease-manifestation in heart valve leaflets occurs at earlier time points than in single Tnf^tm2Gkl heterozygotes

• an increase of T and B cell infiltration is seen in late stages of the disease in the aortic valve leaflets compared to single Tnf^tm2Gkl heterozygotes

cardiac fibrosis ( J:264147 )

• mice exhibit exacerbated aortic valve fibrosis compared to in single Tnf^tm2Gkl heterozygotes

aortic valve inflammation ( J:264147 )

• an increase of T and B cell infiltration is seen in late stages of the disease in the aortic valve leaflets compared to single Tnf^tm2Gkl heterozygotes

skeleton

arthritis ( J:264147 )

• mice exhibit a more aggressive and destructive type of arthritis, exacerbated synovial hyperplasia, and bone destruction compared to single Tnf^tm2Gkl heterozygotes

• disease-manifestation in joints occurs at earlier time points than in single Tnf^tm2Gkl heterozygotes

• an increase of T and B cell infiltration is seen in late stages of the disease in the ankle joint compared to single Tnf^tm2Gkl heterozygotes

cellular

abnormal cell physiology ( J:264147 )

• valvular interstitial cells fail to become activated

• however, cultured valvular interstitial cells appear similar to wild-type cells and exhibit normal proliferation

abnormal cell adhesion ( J:264147 )

abnormal fibroblast physiology ( J:264147 )

• synovial fibroblasts fail to become activated

• however, cultured synovial fibroblasts appear similar to wild-type cells and exhibit normal proliferation

homeostasis/metabolism

increased circulating tumor necrosis factor level ( J:264147 )

• circulating TNF levels are elevated

abnormal wound healing ( J:264147 )

• synovial fibroblasts and valvular interstitial cells show only 40-45% closure of a wound in culture compared to 70-80% closure in single Tnf^tm2Gkl heterozygotes and about 20% closure in wild-type cells

immune system

aortic valve inflammation ( J:264147 )

• an increase of T and B cell infiltration is seen in late stages of the disease in the aortic valve leaflets compared to single Tnf^tm2Gkl heterozygotes

increased circulating tumor necrosis factor level ( J:264147 )

• circulating TNF levels are elevated

increased tumor necrosis factor secretion ( J:264147 )

• levels of secreted TNF-alpha in supernatants of cultured synovial fibroblasts and valvular interstitial cells are elevated

arthritis ( J:264147 )

• mice exhibit a more aggressive and destructive type of arthritis, exacerbated synovial hyperplasia, and bone destruction compared to single Tnf^tm2Gkl heterozygotes

• disease-manifestation in joints occurs at earlier time points than in single Tnf^tm2Gkl heterozygotes

• an increase of T and B cell infiltration is seen in late stages of the disease in the ankle joint compared to single Tnf^tm2Gkl heterozygotes

Contributing Projects: Mouse Genome Database (MGD), Gene Expression Database (GXD), Mouse Models of Human Cancer database (MMHCdb) (formerly Mouse Tumor Biology (MTB)), Gene Ontology (GO)
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